ABSTRACT This Mentored Patient-Oriented Research Career Development Award proposal will provide an excellent educational environment, expert mentorship, and didactic and practical training to facilitate Dr. Matthew Kelly?s development as an independent investigator. Dr. Kelly?s long-term career goal is to develop strategies that use targeted manipulation of the microbiome to prevent and treat infections in children. The proposed research, involving mother-infant pairs in Botswana, will provide insight into the potential impact of the nasopharyngeal microbiome on the risk of childhood pneumonia. Pneumonia is the leading infectious killer of children globally, accounting for 920,000 deaths each year. More than half of these deaths occur in sub-Saharan Africa. Colonization of the nasopharynx precedes pneumonia caused by bacterial pathogens, and the nasopharyngeal microbiome may serve as a barrier to colonization and invasion of the lower respiratory tract by these bacteria. In this proposal, Dr. Kelly will use Streptococcus pneumoniae as a model to further knowledge of the dynamic interactions between the nasopharyngeal microbiome and bacterial respiratory pathogens. He will also develop a systematic approach for the application of conventional multivariable statistics to the analysis of longitudinal microbiome data. The candidate is an Assistant Professor of Pediatrics in the Division of Infectious Diseases at Duke University. He was previously the Africa Fellow in the David N. Pincus Global Health Fellowship through the Children?s Hospital of Philadelphia, and has been conducting clinical research studies in Botswana since 2012. Dr. Kelly?s short-term goals for the K23 program are: 1) acquire bioinformatics and computational biology skills for the analysis of microbiome sequencing data; 2) obtain additional expertise in the design and conduct of prospective clinical studies in children; and 3) develop a model for use of conventional multivariable statistical methods in analyses of longitudinal microbiome data. Dr. Kelly?s mentorship team has expertise in the microbiome, bioinformatics, conventional multivariable statistics, and global health research, and a history of successful mentorship of junior faculty. Dr. Kelly?s primary mentor, Dr. Rawls, leads an NIH-funded research program studying the microbiome and host-microbe interactions. His co-mentors, Drs. Cunningham and Hudgens, have expertise in the conduct of international clinical research and the development of novel statistical methodologies for studies of infectious diseases, respectively. His external advisor, Dr. Steenhoff, has more than 10 years of clinical research experience in Botswana and will assist with study implementation. The remaining members of Dr. Kelly?s external advisory committee are experts in the early infant microbiome (Seed) and pediatric pneumonia (Shah). The proposed research could ultimately lead to development of the first rationally- designed probiotics for the prevention of pneumonia and other respiratory infections. Upon completion of the career development and research plans, Dr. Kelly will have the necessary skillset to lead clinical studies that use targeted manipulation of the microbiome for the prevention and treatment of infections in children.